The statin class of drugs has been shown to reduce stroke and myocardial infarction in patients with hypercholesterolemia. Intriguingly, the statins have been shown to accomplish this not only by reducing cholesterol levels, but also by improving nitric oxide bioactivity and thereby reversing endothelial dysfunction in human subjects. Atorvastatin is one of the most widely prescribed drugs in the United States, with a well-characterized and very acceptable side effect profile. Our group and others have published evidence that approximately half of patients with sickle cell disease have physiological and biochemical evidence of impaired nitric oxide bioavailability. This appears to contribute to impaired regional blood flow in patients with sickle cell disease, particularly during vaso-occlusive episodes. Therefore, it is attractive to test atorvastatin for its hypothetical ability to restore nitric oxide dependent blood flow in patients with sickle cell disease. We are measuring forearm blood flow by plethysmography to determine the response to infusion of L-NMMA, a nitric oxide synthase inhibitor, to which sickle cell patients have a blunted response. After four weeks of oral outpatient atorvastatin therapy, this study is repeated, with increased responsiveness to L-NMMA as the primary outcome variable. Atorvastatin-induced alterations in blood flow to acetylcholine and to nitroprusside are also being evaluated. Additional secondary studies are evaluating the degree to which the elevated level of xanthine oxidase in sickle cell patients inhibit nitric oxide-mediated blood flow; markers of inflammation and oxidation; and gene expression by microarray and pilot studies of proteomics in sickle cell patients. As of 28 October 2003, we obtained IRB approval to begin these studies. We began enrollment in March 2004. We have enrolled 13 subjects and have completed 8 studies. Four studies are currently in progress with another 1 planned to begin within the next month. In preliminary analysis of studies to date, initial average perk sodium nitroprusside (SNP) vasodilation response over baseline is 90%, well below estimated control values of 200-300%. After 4 weeks of atorvastatin, the average peak SNP vasodilation response has increased to approximately 190%. We plan to evaluate up to 25 subjects, with an interim analysis at 15 patients. These physiological translational studies will determine whether additional studies of statins should be performed to evaluate the efficacy of statins to reduce the clinical severity of sickle cell disease.